Pursuant to 37 C.F.R. xc2xa71.71(e), Applicants note that a portion of this disclosure contains material which is subject to copyright protection. The copyright owner has no objection to the facsimile reproduction by anyone of the patent document or patent disclosure, as it appears in the Patent and Trademark Office patent file or records, but otherwise reserves all copyright rights whatsoever.
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Modern techniques for identifying compounds with desired chemical or physical properties typically involve assembling complex libraries of compounds that are systematically screened to isolate members having the desired properties. One general approach to library construction involves creating compounds using combinatorial, parallel, or other synthetic processes in which sets of compounds are prepared from sets of building blocks, e.g., via multi-step solution- or solid-phase synthesis. For example, split/pool combinatorial synthetic techniques can be used to produce all possible combinations of a set of building blocks. In particular, the methods typically include splitting an initial pool of solid supports with attached chemical moieties into a selected number of individual pools. Each pool is subjected to a first randomization reaction that generates a different modification to the solid supports in each separate pool. Following this first set of reactions, the individual pools of solid supports are typically combined, mixed, and split once again into separate pools. Each split pool is then subjected to a second randomization, which again is different for each pool. This process is repeated until the desired library of target compounds is produced. Additional details relating to library synthesis using combinatorial and parallel approaches are described in, e.g., Houghten (2000) xe2x80x9cParallel array and mixture-based synthetic combinatorial chemistry: Tools for the next millennium,xe2x80x9d Annu. Rev. Pharmacol. Toxicol. 40:273-282, Thompson (2000) xe2x80x9cRecent applications of polymer-supported reagents and scavengers in combinatorial, parallel, or multistep synthesis,xe2x80x9d Curr. Opin. Chem. Biol. 4:324-337, Bunin et al. (1999) xe2x80x9cApplication of combinatorial and parallel synthesis to medicinal chemistry,xe2x80x9d Annu. Rep. Med. Chem. 34:267-286, and Brooking et al. (1999) xe2x80x9cSplit-split. A multiple synthesiser approach to efficient automated parallel synthesis, Tetrahedron Lett. 40(7):1405-1408.
A standard tool for parallel chemistry, including randomization steps in combinatorial protocols, such as split/pool synthesis, is the multiple well reaction vessel that typically includes a collection of tubes or a reaction block bored out with a designated number of reaction wells or holes. These reaction wells are generally fitted with a filter at one end, which allows the individual wells to be employed for solid-liquid separations or other purification processes. The footprint of such reaction blocks typically corresponds to an array of wells in a standard micro-well assay plate. A series of individually addressable open reactors is generally formed within a reaction block by contacting a gasket to the bottom or outlets of the reaction wells. In addition, a series of enclosed reactors is typically made by sealing the top or inlets to the reaction wells with another gasket. Sealed reaction wells provide for aggressive agitation of well contents and for the use of extreme reaction conditions.
Sub-optimal sealing and clamping mechanisms inhibit throughput in multiple well reaction vessels of the prior art. Specifically, preexisting technologies typically require users to operate a series of latches, screws, and/or other fasteners, which hinders safe and efficient access to reaction chambers. Further, the clamping mechanisms of these devices generally do not provide secure reaction well seals such that leakage of materials from the reaction wells commonly results. Sample leakage typically causes reaction failure for the reaction within the particular well from which the leakage occurred and/or cross-contamination among multiple reaction wells. One source of leakage in preexisting devices is uneven clamp load over the reaction wells. In addition, the inferior designs that characterize the prior art also suffer from general losses of clamp load over time, which further contributes to the aforementioned leakage-related problems.
From the above, it is apparent that there is a substantial need for new parallel reaction devices that permit efficient and rapid access to reaction wells. It would also be desirable to have reaction blocks that remain securely sealed under diverse reaction conditions, including varied extremes of temperature and agitation. These and a variety of additional features of the present invention will become evident upon complete review of the following.
The present invention relates to devices for performing multiple reactions, such as combinatorial synthesis reactions, or other processes in parallel. More specifically, the invention provides parallel reaction devices that include secure and efficient sealing or clamping mechanisms, which significantly improve throughput relative to existing devices. The devices of the invention incorporate reaction blocks that include arrays of reaction wells. Reaction blocks are sometimes disposable or at least not intended for indefinite use. In addition to reaction blocks, the devices of the present invention include lids and gaskets for sealing reaction wells within the reaction blocks and attachment components for attaching the lids to the reaction blocks. In preferred embodiments, lids include arrays of protrusions that axially align with reaction wells in assembled devices to further enhance reaction well seals. The lids of the devices of the invention are also typically removably attached to reaction blocks and produce substantially even clamp loads across inlet or outlet portions of reaction blocks. Reaction block containers, systems, and kits that include these devices or device components are additionally provided.
In one aspect, the invention provides a parallel reaction device that includes (a) a reaction block that includes an array of reaction wells in which at least one reaction well in the array is disposed through the reaction block, which reaction well includes an inlet portion and an outlet portion, (b) a top lid attached to the reaction block by at least one top attachment component, which top lid includes at least one protrusion disposed on a surface that engages the reaction block, which protrusion presses a top gasket into contact with the inlet portion of the reaction well to seal the inlet portion, and (c) a bottom lid attached to the reaction block by at least one bottom attachment component, which bottom lid presses a bottom gasket into contact with the outlet portion of the reaction well to seal the outlet portion.
In another aspect, the invention relates to a parallel reaction device that includes (a) a reaction block that includes an array of reaction wells, wherein at least one reaction well in the array is disposed through the reaction block, which reaction well includes an inlet portion and an outlet portion, (b) a top lid attached to the reaction block by at least one top hinge component and at least one top latch component, which top lid presses a top gasket into contact with the inlet portion to the reaction well to seal the inlet portion, and (c) a bottom lid attached to the reaction block by at least one bottom hinge component and at least one bottom latch component, which bottom lid presses a bottom gasket into contact with the outlet portion of the reaction well to seal the outlet portion.
In yet another aspect, the invention provides a parallel reaction device that includes (a) a reaction block that includes an array of reaction wells in which at least one reaction well in the array is disposed through the reaction block, which reaction well includes an inlet portion and an outlet portion, (b) a top lid attached to the reaction block by at least one top hinge component and at least one top latch component, which top lid includes at least one protrusion disposed on a surface that engages the reaction block, which protrusion presses a top gasket into contact with the inlet portion to the reaction well to seal the inlet portion, and (c) a bottom lid attached to the reaction block by at least one bottom hinge component and at least one bottom latch component, which bottom lid presses a bottom gasket into contact with the outlet portion of the reaction well to seal the outlet portion.
The reaction blocks of the present invention include various embodiments. For example, reaction blocks optionally include cavities disposed between and proximal to inlet portions of adjacent reaction wells to direct fluidic materials away from other inlet portions. In certain preferred embodiments, each reaction well is disposed through the reaction block. In other preferred embodiments, one or more reaction wells further include a filter disposed therein. Optionally, at least two regions of the reaction well include different inner or outer cross-sectional dimensions. Further, outlet portions of the array of reaction wells typically include a footprint that corresponds to wells of a micro-well plate. In addition, the outlet portion generally includes an outlet spout having a smaller inner cross-sectional dimension than other regions of the reaction well in which a transition area between the outlet spout and the other regions in the reaction well is, e.g., abrupt, tapered, stepped, or the like.
In preferred embodiments, reaction blocks include at least one pair of substantially opposing recessed regions disposed in opposing surfaces of the reaction block proximal to a midpoint of each surface, which opposing recessed regions mount the top and bottom attachment components. In these embodiments, the top and bottom attachment components typically include (i) a band disposed around the reaction block in the opposing recessed regions in which the band includes at least one first top hinge component, at least one first top latch component, at least one first bottom hinge component, and at least one first bottom latch component, (ii) at least one second top hinge component and at least one second top latch component attached to the top lid in which the second top hinge component(s) removably engage(s) the first top hinge component(s) and the second top latch component(s) removably engage(s) the first top latch component(s), and (iii) at least one second bottom hinge component and at least one second bottom latch component(s) attached to the bottom lid in which the second bottom hinge component(s) removably engage(s) the first bottom hinge component(s) and the second bottom latch component(s) removably engage(s) the first bottom latch component(s). Each hinge component optionally independently includes, e.g., a male or a female lift-off hinge component, whereas each latch component optionally independently includes, e.g., a latch body (e.g., a rotatable draw latch body or the like) or a keeper plate.
The present invention also relates to a lid that includes at least one protrusion capable of pressing a gasket into contact with at least a portion of at least one reaction well of a reaction block that includes an array of reaction wells to seal (e.g., radially seal or the like) the reaction well when the lid is attached to the reaction block. In particular, the protrusion prevents leakage of fluidic materials from the inlet portion to reduce cross-contamination among the reaction wells. The lid typically includes an array of protrusions corresponding to the array of reaction wells. Optionally, the lid further includes an array of apertures disposed through the lid in which at least one aperture (e.g., a tapered aperture, etc.) axially aligns with the reaction well. For example, each member of the array of apertures generally axially aligns with a different reaction well. Fluidic materials are optionally introduced into reaction wells through apertures and gaskets through a needle (e.g., a syringe needle or the like). Further, the protrusion optionally includes a protruding annular ridge disposed around the aperture. The lid also typically further includes at least one attachment component (e.g., at least one latch and at least one hinge, or the like) to attach the lid to the reaction block.
The invention additionally relates to a lid that includes at least one latch component and at least one hinge component, which hinge component is capable of engaging at least one other hinge component and which latch component is capable of removably engaging at least one other latch component, which other hinge and other latch components are attached to a reaction block. Optionally, the lid further includes at least one protrusion disposed on a surface of the lid, which protrusion presses a gasket into contact with at least a portion of at least one reaction well of the reaction block. For example, the lid optionally includes an array of protrusions corresponding to an array of reaction wells disposed in the reaction block. In another embodiment, the lid further includes an array of apertures disposed through the lid in which at least one aperture (e.g., a tapered aperture, etc.) axially aligns with the reaction well. Typically, each member of the array of apertures axially aligns with a different reaction well.
The top and bottom gaskets typically include sheets of gasketing material. The top gasket optionally includes at least one protrusion, which protrusion axially aligns with the inlet portion. As an additional option, the bottom gasket includes at least one protrusion, which protrusion axially aligns with the outlet portion. For example, at least one of the top and bottom gaskets optionally includes an array of protrusions in which at least one protrusion axially aligns with the reaction well.